. Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-15. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. This is a very interesting finding, a remarkable result with real therapeutic potential. Previous studies had suggested that the β amyloid peptide can interact with α7-containing nicotinic receptors and that it may hijack signaling through the receptor to exert negative effects on neurons. How this occurs and what significance it might have for Alzheimer disease have been matters of some contention. Using genetically engineered mice that produce a precursor protein (APP) of the β amyloid peptide, Dziewczapolski et al. clearly show that the α7-receptor gene product is necessary for the mice to display key behavioral deficits reminiscent of Alzheimer disease. Deleting the α7 gene enables the mice to behave nearly the same as wild-type (control) mice in the assays. In addition to providing strong evidence for a physiologically relevant pathway, the results are exciting because they identify a possible target for drug intervention. Specific antagonists that inhibit only α7-containing nicotinic receptors may have substantial benefit for slowing progression of the disease. Partial agonists may offer a different strategy, given the desensitization features of the receptor. Such compounds already exist, but designing variants that are effective, specific, and able to cross the blood-brain barrier will pose challenges for the future. A different, but also interesting challenge, will be the elucidation of how α7-containing receptors enable APP products to exert their behavioral effects.

  2. This very interesting paper by Dziewczapolski et al. provides further evidence for the involvement of α7 nicotinic acetylcholine receptors in either mediating or contributing to the pathogenesis of Aβ-induced biochemical and behavioral pathology. The paper shows that knockout of the α7 nicotinic receptor mitigates biochemical pathology and the cognitive and LTP deficits in APP transgenic mice. The study, therefore, provides further support for the view that selective inhibitors of the α7 nicotinic receptor may have value in the treatment of Alzheimer disease.

    The precise mechanism that causes the amelioration of Aβ's effects is less certain. One possibility is that Aβ binds to the α7 nicotinic receptor, which, in turn, directly causes the neurotoxic effects (Wang et al., 2000; Wang et al., 2000; Wang et al., 2003). There are several studies which support this notion. The observations of Dineley et al. (2001), and Snyder et al. (2005) are consistent with this hypothesis. Our own work (Fodero et al., 2004) found that α7 nicotinic receptors are needed for an Aβ-induced increase in a minor glycoform of acetylcholinesterase that is selectively elevated in Alzheimer disease brain. However, in our own studies, we were unable to reach the conclusion of Wang et al. that Aβ binds directly to the α7 nicotinic receptor, despite having tested this idea repeatedly in a variety of experimental paradigms (brain homogenate and tissue slice binding assays, Xenopus oocyte expression system, functional assays) (Small et al., 2007).

    Another possibility that deserves serious consideration is the idea that the α7 nicotinic receptor may facilitate Aβ's effects, without being a direct mediator. Aβ is known to increase calcium permeability of the plasma membrane and the α7 receptor is also permeable to calcium. Thus, activation of the α7 receptor may contribute synergistically to calcium-induced neurotoxicity and dysfunction. This concept is elaborated in a recent article (Small, 2008), in which it is speculated that the α7 nicotinic acetylcholine receptor contributes to the progression of Alzheimer disease through a mechanism involving synaptic scaling. Changes in the level of α7 receptor may be due to altered activity of neural networks, rather than to any direct effect of Aβ on the receptor itself.

    Whatever the mechanism involved, this paper by Dziewczapolski et al. strengthens the case for considering α7 nicotinic acetylcholine receptors as an important target for Alzheimer disease therapeutics. Whether such a strategy will be free of unwanted side effects is unclear. However, as α7 receptors are neuromodulatory and function more in the regulation of synaptic plasticity than in direct neurotransmission, this possibility seems increasingly likely.

    References:

    . beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. J Biol Chem. 2000 Feb 25;275(8):5626-32. PubMed.

    . Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem. 2000 Sep;75(3):1155-61. PubMed.

    . Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547-53. PubMed.

    . Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: In vitro and in vivo mechanisms related to Alzheimer's disease. J Neurosci. 2001 Jun 15;21(12):4125-33. PubMed.

    . Alpha7-nicotinic acetylcholine receptors mediate an Abeta(1-42)-induced increase in the level of acetylcholinesterase in primary cortical neurones. J Neurochem. 2004 Mar;88(5):1186-93. PubMed.

    . The beta-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the alpha7 nicotinic acetylcholine receptor. J Neurochem. 2007 Jun;101(6):1527-38. PubMed.

    . Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression?. Trends Mol Med. 2008 Mar;14(3):103-8. PubMed.